In August, 2000, Rare Disease Control and Orphan Drug Act was promulgated, in which associated regulations about rare diseases were formulated. By Dec. 31, 2015, the National Health Department, Ministry of Health and Welfare Department of the Executive Yuan announced a total of 205 rare diseases. Spinocerebellar ataxia is one of the rare genetic diseases, and included in the major injury and disease category 07, with a rare disease classification serial number 334.3. The prevalence of spinocerebellar ataxia varies from species to species and from country to country. The incidence in the United States is estimated to be about 3-5 cases in every 100,000 people, and about 10 thousands of people suffer from spinocerebellar ataxia in Taiwan, constituting the largest population among all the people with various rare diseases.
At present, there is no effective diagnosis and treatment for spinocerebellar ataxia, and the symptoms are relieved and the deterioration of the disease is slowed down only through a variety of rehabilitation treatments. Therefore, it is necessary to develop a drug for the diagnosis and treatment of spinocerebellar ataxia, in which a histone deacetylase (HDAC) inhibitor having the effect of modifying transcriptional disorder is of great potential.
HDAC mainly functions to deacylate the lysine on the histone protein, and affects the function of intracellular proteins. When the HDAC activity is out of balance, many diseases, such as cancers and neurodegenerative diseases are caused.
Depending on different structures, the HDAC inhibitors are divided into four types, including hydroxamic acid-based, cyclotetrapeptide-based, phenyl amide-based and short chain fatty acid-based HDAC inhibitors. Among them, the hydroxamic acid-based HDAC inhibitors SAHA (Vorinostat, Zolinza™, Merk) and Belinostat (PXD101, Novartis) are approved by FDA respectively in 2006 and 2014 for treating T cell lymphoma, which can also exhibit good therapeutic effect in the treatment of a variety of cancers while the injury to normal tissues is little. It is further pointed out in literatures that the symptoms can be improved by targeting HDAC in the treatment of neurodegenerative diseases.
The HDAC inhibitor is labeled with a radioactive isotope by a radiochemical method, and the distribution of the agent in vivo is traced by non-invasive imaging to evaluate the therapeutic effect during the treatment of diseases. This facilitates the development of new drugs of such inhibitors. Among a variety of radioactive isotopes, fluorine-18 is most widely used in the research of nuclear medicine and in clinic, and considered as a desirable nuclide for non-invasive imaging, due to the good properties such as suitable half-life (110 minutes) such that there is sufficient time to carry out the above-mentioned relatively complex chemical synthesis steps, and a high-resolution image can be obtained. After being injected to the lateral ventricles of animals, the fluorine-18-hydroxamic acid-based compound can target a focus of spinocerebellar ataxia with over-activation of HDAC, and a positron emission tomography (PET) image is obtained by taking advantage of the radioactivity of fluorine-18, thus providing early diagnosis or evaluation for the therapeutic effect during the treatment of diseases.
The studies on detection of over activated HDAC by using the fluorine-18 labeling technology in related art include “Non-invasive imaging for histone deacetylase with contrast agent fluorine-18-FAHA for cancer cells in animals”, Uday et al. J. Label. Compd. Radiopharm; 49: 997-1006, 2006.
However, fluorine-18-FAHA has the disadvantage of rapid metabolization into fluoro-18-fluoroacetate (FAC) in vivo. This metabolite is easily absorbed by the glial cells or peripheral tissue, such that the imaging results are affected, and whether the radioactive isotope fluorine detected by the image is the distribution of fluorine 18-FAHA or fluorine 18-FAC cannot be determined. In addition, fluorine 18-FAHA does not have the functional group acylhydroxylamine, and can only sever as a substrate, rather than an inhibitor, of HDAC.
In 2011, J. Adam Hendricks et al proposed a method for preparing fluorine-18-SAHA (J Med Chem. 11; 54(15): 5576-5582.), in which fluorine-18-SAHA is determined to have a HDAC inhibition function, and confirmed to have a targeting effect in a tumor animal model. However, there are still limitations on fluorine-18-SAHA. Because SAHA is a broad-spectrum inhibitor and has an inhibitory effect on all the subgroups of HDAC, it is difficult to distinguish the role of individual subtypes in the development of diseases. Moreover, the process for labeling with fluorine-18 comprises 3-step synthesis including fluorination of aniline, bonding with dimethyl suberate, and formation of hydroxamic acid, as well as purification. The operation steps are complex, the risk of exposure to radiation is increased, and the radioactive labeling yield is quite low.
In view of this, there is unmet need for developing a new hydroxamic acid-based contrast agent containing an isotope of fluorine, to solve the above problems.